QSRR model of reactivity for Parham cyclization reactions

Parham reaction is very important route for the synthesis of heterocyclic compounds, which consists of the intramolecular reaction of aryllithiums generated by lithium–halogen exchange with different types of internal electrophiles.¹ In this paper we collected a dataset of >100 reactions for many substrates and internal electrophiles (mainly, amides and esters) with a wide range of reaction yields (0 – 99%). The reactions have been carried out in many different experimental conditions with different values non-structural variables (δ_k) like: temperature of addition, addition time, organolithium equivalents, reaction times, and reaction temperature. Next, we calculated many structural and/or physicochemical variables (V_k) for the substrates and products of the reaction. After that, we constructed a Quantitative Structure-Reactivity Relationship (QSRR) model² able to predict the yield of reaction under many different conditions with acceptable accuracy. We also carried a 10.000-points simulation of the reaction conditions.

References

1. a) Ruiz, J.; Sotomayor, N.; Lete, E. Org. Lett. 2003, 5, 1115. b) Ruiz, J.; Ardeo, A.; Ignacio, R.; Sotomayor, N.; Lete, E. Tetrahedron 2005, 61, 3311. For a review, see: Sotomayor, N.; Lete, E. Curr. Org. Chem. 2003, 7, 275.

2. For related examples of our work; see: a) Blázquez-Barbadillo, C.; Aranzamendi, E.; Coya, E.; Lete, E.; Sotomayor, N.; González-Díaz, H. RSC Adv. 2016; 6, 38602. b) Aranzamendi, E.; Arrasate, S.; Lete, E.; Sotomayor, N.; González-Díaz, H. ChemistryOpen 2016, http://dx.doi.org/10.1002/open.201600120.